Britta Siegmund

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

Are you Britta Siegmund?

Claim your profile

Publications (156)678.52 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: IL-17-producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A-producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS (-/-) Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS (-/-) mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The cell adhesion molecule CD2 facilitates antigen-independent T-cell activation and CD2 deficiency or blockade reduces intestinal inflammation in murine models. We here aimed to evaluate the therapeutic potential of monoclonal antibodies (mAb) specific for human CD2 in colitis treatment. Transfer colitis induced by naϊve CD4+ T cells expressing human CD2 was treated with anti-human CD2 mAb. The mAb CB.219 protected from severe colitis in a preventive treatment regimen, while therapeutic treatment ameliorated intestinal inflammation. Diminished intestinal tissue damage was paralleled by a profound suppression of lamina propria lymphocytes to produce proinflammatory cytokines and tumor necrosis factor α as well as the neutrophil chemoattractant CXC motif ligand 1 and the CC chemokine ligand 3. Furthermore, infiltration with macrophages and T cells was low. Thus, reduced intestinal inflammation in our humanized colitis model by targeting CD2 on T cells with the mAb CB.219 suggests a novel approach for colitis treatment.
    Clinical Immunology. 01/2015;
  • Source
    Zeitschrift für Gastroenterologie. 12/2014; 52(12):1431-84.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided. © Georg Thieme Verlag KG Stuttgart · New York.
    Zeitschrift für Gastroenterologie. 12/2014; 52(12):1423-30.
  • Source
    Lea I Kredel, Britta Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier.
    Frontiers in Immunology 09/2014; 5:462.
  • LeaI Kredel, Arvind Batra, Britta Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine.
    Current Opinion in Gastroenterology 09/2014; · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early enteral nutrition is recommended for patients in intensive care units, but nutrition provision is often hindered by a variety of unit-specific problems.
    American Journal of Critical Care 09/2014; 23(5):396-403. · 1.60 Impact Factor
  • J Maul, B Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic inflammatory bowel diseases are mainly represented by Crohn's disease and ulcerative colitis. Current epidemiological data indicate a rise in incidence over the last five decades in the Western world. Consequently resulting not only in the reconsideration of the pathogenesis of inflammatory bowel diseases but furthermore emphasizing the need for a curative approach. With this review we aim to provide a concise overview on pathogenesis, diagnostics as well as therapy with a particular focus on medical strategies after ileocecal resection in Crohn's disease. In the end the near future with regard to therapeutic strategies to be introduced into daily clinical work will be described.
    Deutsche medizinische Wochenschrift (1946). 09/2014; 139(36):1771-1775.
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). · 1.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating interstudy comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease.
    International journal of clinical and experimental pathology 08/2014; 7(8):4557-4576. · 1.78 Impact Factor
  • Lea-Maxie Haag, Britta Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory bowel diseases (IBD) with its two major forms Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing disorders leading to inflammation of the gastrointestinal tract. Although the precise aetiology of IBD remains unclear, several factors are believed to contribute to disease pathogenesis. Among these, the role of the intestinal microbiota has become more and more appreciated. Evidence from experimental and clinical studies strongly suggests that chronic intestinal inflammation results from a dysregulated immune response towards components of the microbiota in genetically susceptible hosts. The growing perception of the microbiota as a major driver of disease pathogenesis raises the question, if the intestinal microbiota can be used as a therapeutic target in CD. Based on what we know about host microbiota interactions in health and disease, the objective of this review is to address the question if the microbiota holds the key to the future therapy in CD.
    Baillière&#x027 s Best Practice and Research in Clinical Gastroenterology 06/2014; · 3.28 Impact Factor
  • B Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: The challenge of the mucosal immune system is to develop tolerance toward intestinal antigens. Considering the quantity of bacteria that continuously attack the intestinal barrier, one can only imagine the complexity involved. To master this task, a tight network between the intestinal microbiota, the barrier, immune cells of the lamina propria as well as the adjacent mesenteric fat tissue is required. The key pathways involved have been revealed by the genome-wide association studies as well as functional data from experimental models. However, although knowledge with regard to the pathogenesis of chronic inflammatory bowel disease has been increasing continuously over recent decades, the current therapeutic strategies are limited to controlling the pro-inflammatory effector phase rather than achieving cure. The best example is cytokine neutralizing antibodies. The present review aims to describe the role of the various cell populations within the intestinal wall for disease pathogenesis and, thus, identify possible therapeutic strategies.
    Der Internist 05/2014; · 0.27 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Severe courses of Crohn's disease (CD) during pregnancy are rare. However, if occurring, the risk of miscarriage and low birth weight is increased. At present, only limited data is available on the treatment of CD during pregnancy. In particular, there are no standard guidelines for surgical therapy. Nevertheless, surgery is often unavoidable if complications during the course of the disease arise. This study provides a critical overview of conventional and interventional treatment options for CD complications during pregnancy and analyses the surgical experience gained thus far. For illustrative purposes, clinical cases of three young women with a severe clinical course during pregnancy are presented. After treatment-refractory for conservative and interventional measures, surgery remained as the only treatment option. In all cases, a split stoma was created after resection to avoid anastomotic leaks that would endanger the lives of mother and child. The postoperative course of all three patients was uneventful, and pregnancy remained intact until delivery. No further CD specific medication was required before birth. The management of CD patients during pregnancy requires close interdisciplinary co-operation between gastroenterologists, obstetricians, anaesthetists and visceral surgeons. For the protection of mother and child treatment should thus be delivered in a specialised centre. This article demonstrates the advantages of surgical therapy by focusing on alleviating CD complaints and preventing postoperative complications.
    International Journal of Colorectal Disease 05/2014; · 2.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: α-Haemolysin (HlyA) influences host cell ionic homeostasis and causes concentration-dependent cell lysis. As a consequence, HlyA-producing Escherichia coli is capable of inducing 'focal leaks' in colon epithelia, through which bacteria and antigens translocate. This study addressed the role of HlyA as a virulence factor in the pathogenesis of colitis according to the 'leaky gut' concept. To study the action of HlyA in the colon, we performed oral administration of HlyA-expressing E coli-536 and its isogenic α-haemolysin-deficient mutant (HDM) in three mouse models: wild type, interleukin-10 knockout mice (IL-10(-/-)) and monoassociated mice. Electrophysiological properties of the colonised colon were characterised in Ussing experiments. Inflammation scores were evaluated and focal leaks in the colon were assessed by confocal laser-scanning microscopy. HlyA quantity in human colon biopsies was measured by quantitative PCR. All three experimental mouse models infected with HlyA-producing E coli-536 showed an increase in focal leak area compared with HDM. This was associated with a decrease in transepithelial electrical resistance and an increase in macromolecule uptake. As a consequence, inflammatory activity index was increased to a higher degree in inflammation-prone mice. Mucosal samples from human colon were E coli HlyA-positive in 19 of 22 patients with ulcerative colitis, 9 of 9 patients with Crohn's disease and 9 of 12 healthy controls. Moreover, focal leaks were found together with 10-fold increased levels of HlyA in active ulcerative colitis. E coli HlyA impairs intestinal barrier function via focal leak induction in the epithelium, thereby intensifying antigen uptake and triggering intestinal inflammation in vulnerable mouse models. Therefore, HlyA-expressing E coli strains should be considered as potential cofactors in the pathogenesis of intestinal inflammation.
    Gut 02/2014; · 13.32 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S36. · 3.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Histone deacetylase (HDAC) inhibitors have primarily been associated with an anti-proliferative effect in vitro and in vivo. Recent data provide evidence for an anti-inflammatory potency of HDAC inhibitors in models of experimental colitis. As the balance of T cell subpopulations is critical for the balance of the mucosal immune system, this study explores the regulatory potency of HDAC inhibitors on T cell polarization as a mechanistic explanation for the anti-inflammatory effects observed. While HDAC inhibition suppressed the polarization towards the pro-inflammatory T helper 17 (Th17) cells, it enhanced forkhead box P3 (FoxP3)+ regulatory T cell polarization in vitro and in vivo at the site of inflammation in the lamina propria. This was paralleled by a down-regulation of the IL-6 receptor (IL 6R) on naive CD4+ T cells on the mRNA as well as on the protein level, and changes in the chromatin acetylation at the IL6R gene and its promoter. Downstream of the IL-6R, HDAC inhibition was followed by a decrease in signal transducer and activation of transcription 3 (STAT3) phosphorylation as well as RAR-related orphan receptor T (RORγT) expression, thus identifying the IL 6/STAT3/IL-17 pathway as an important target of HDAC inhibitors. These results directly translated to experimental colitis, where the IL-6R expression was suppressed in naive T cells, paralleled by a significant reduction of Th17 cells in the lamina propria of ITF2357-treated animals resulting in amelioration of disease. The present study indicates that in experimental colitis inhibition of HDAC exerts an anti-inflammatory potency by directing T helper cell polarization via targeting the IL-6 pathway.
    Journal of Biological Chemistry 01/2014; · 4.60 Impact Factor
  • Source
    Tassilo Kruis, Arvind Batra, Britta Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the last decade it became broadly recognized that adipokines and thus the fat tissue compartment exert a regulatory function on the immune system. Our own group described the pro-inflammatory function of the adipokine leptin within intestinal inflammation in a variety of animal models. Following-up on this initial work, the aim was to reveal stimuli and mechanisms involved in the activation of the fat tissue compartment and the subsequent release of adipokines and other mediators paralleled by the infiltration of immune cells. This review will summarize the current literature on the possible role of the mesenteric fat tissue in intestinal inflammation with a focus on Crohn's disease (CD). CD is of particular interest in this context since the transmural intestinal inflammation has been associated with a characteristic hypertrophy of the mesenteric fat, a phenomenon called "creeping fat." The review will address three consecutive questions: (i) What is inducing adipocyte activation, (ii) which factors are released after activation and what are the consequences for the local fat tissue compartment and infiltrating cells; (iii) do the answers generated before allow for an explanation of the role of the mesenteric fat tissue within intestinal inflammation? With this review we will provide a working model indicating a close interaction in between bacterial translocation, activation of the adipocytes, and subsequent direction of the infiltrating immune cells. In summary, the models system mesenteric fat indicates a unique way how adipocytes can directly interact with the immune system.
    Frontiers in Immunology 01/2014; 4:510.
  • Dr. J. Maul, B. Siegmund
    [Show abstract] [Hide abstract]
    ABSTRACT: Bei einem Großteil der Patienten mit einem Morbus Crohn wird im Krankheitsverlauf die Indikation zu einer Darmresektion gestellt. Für den Gastroenterologen stellt sich postoperativ die Frage der Nachsorge bzw. der Einleitung einer immunsuppressiven Therapie. Mit der vorliegenden Übersicht soll basierend auf den aktuellen Leitlinien ein Vorgehen für die klinische Praxis dargestellt werden. Risikofaktoren für ein postoperatives Rezidiv sind Rauchen, frühere intestinale Operationen, penetrierende oder perianale Erkrankung sowie ausgedehnte Dünndarmresektionen. Gleichermaßen ist das Rezidivrisiko bei Vorliegen von Zeichen der Entzündung im Bereich der Anastomose deutlich erhöht (mehr als 5 Aphthen, Rutgeerts-Score ≥ i2). Liegen keine Risikofaktoren vor, so wird daher die Durchführung einer endoskopischen Evaluation der Anastomose 6–12 Monate postoperativ empfohlen. Bei Niedrigrisikopatienten kann eine Mesalazinprophylaxe durchgeführt werden. Bei Patienten mit mehreren Risikofaktoren oder entzündlichen Veränderungen an der Anastomose sollte eine Prophylaxe mit Azathioprin oder eine Therapie mit einem TNF-α-Antikörper in Abhängigkeit vom Therapieansprechen in der Anamnese begonnen werden. Ziel aktueller Untersuchungen ist es, das Rezidivrisiko basierend auf Risikofaktoren oder endoskopischen Entzündungszeichen sowie den Nutzen einer medikamentösen Rezidivprophylaxe besser zu definieren.
    Der Gastroenterologe 01/2014; 8(3).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Einleitung Die Koloproktomukosektomie (CPM) gilt als Verfahren der Wahl für die chirurgische Therapie der Colitis ulcerosa (CU). Bei ausgeprägter Immunsuppression (IS) wird dabei häufig ein dreizeitiges (3Z) Vorgehen gewählt, bei dem eine subtotale Kolektomie der ileoanalen Pouchanlage (IPAA) und abschließenden Ileostomarückverlagerung vorangestellt wird. Im Vergleich zum zweizeitigen (2Z) Vorgehen wird dadurch eine Reduktion der perioperativen Komplikationen erwartet, allerdings ist ein zusätzlicher stationärer Aufenthalt und operativer Eingriff erforderlich. Ziel der hier vorliegenden Studie war es, die beiden Vorgehensweisen im Hinblick auf das klinische Outcome nach IPAA zu vergleichen, um die tatsächliche Effektivität dieser beiden Konzepte überprüfen zu können. Patienten und Methoden Zwischen 1997 und 2010 wurden insgesamt 225 Patienten mit IPAA operiert und einem 2Z oder 3Z Verfahren unterzogen. Zur Erfassung des klinischen Outcomes wurde der operative Schritt der Pouchanlage und IPAA gewertet. Die Datenerhebung erfolgte im Rahmen einer prospektiven Studiendokumentation. Ergebnisse Von 225 Patienten mit CPM mussten 66 aufgrund einer anderen Diagnose als CU (FAP, Colitis indeterminata, Morbus Crohn) sowie Patienten mit definitiver ILS-Anlage ohne Möglichkeit oder Wunsch einer IPAA (n = 54) ausgeschlossen werden. Untersucht wurden 71 Patienten mit einem 2Z (w = 30, m = 41) und 34 Patienten mit einem 3Z Vorgehen (w = 21, m = 13). Das 3Z Vorgehen wies im Vergleich zum 2Z eine kürzere Operationszeit (246 vs. 296 min; p < 0,05), kürzere Liegedauer (15,5 vs. 24,6 Tage; p < 0,05), kürzeren Intensivaufenthalt (3,3 vs. 7,2 Tage; p < 0,05) und weniger Majorkomplikationen auf (5,9 % vs. 22,5 %; p = 0,035). Patienten mit 3Z Vorgehen zeigten einen höheren BMI (26,2 vs. 23,1 kg/m2; p < 0,05) und nahmen weniger IS ein (10 % vs. 62 %; p < 0,05). Schlussfolgerung Die Entscheidung zu einem 3Z Vorgehen bei CU und ausgeprägter IS ist sinnvoll und gerechtfertigt. Durch dieses Vorgehen werden die Immunsuppression sowie deren Einfluss auf die perioperative Morbidität reduziert. Somit kann die IPAA mit kürzerer Operationsdauer, kürzerer Liegedauer und weniger Majorkomplikationen durchgeführt werden.
    Der Chirurg 09/2013; · 0.52 Impact Factor
  • Gut 07/2013; · 13.32 Impact Factor

Publication Stats

3k Citations
678.52 Total Impact Points


  • 2004–2015
    • Charité Universitätsmedizin Berlin
      • • Medical Department, Division of Hepatology and Gastroenterology
      • • Department of Gastroenterology, Infectiology and Rheumatology
      • • Institute of Health Sciences Education and Nursing Science
      • • Institute of Medical Informatics
      Berlín, Berlin, Germany
    • Mental Health Center of Denver
      Denver, Colorado, United States
  • 2008
    • St. Marien- und St. Annastiftskrankenhaus
      Ludwigshafen, Rheinland-Pfalz, Germany
  • 2001–2006
    • University of Colorado
      • Department of Medicine
      Denver, CO, United States
  • 2005
    • University Hospital of Lausanne
      • Institut universitaire de pathologie
      Lausanne, VD, Switzerland
  • 2003
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1997–2001
    • Ludwig-Maximilian-University of Munich
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine II
      München, Bavaria, Germany